New gamma-hydroxy-carboxylic acid amides and process for their manufacture



United States Patent Ofitice The present invention relates to therapeutically valuable, especially narcctically effective new v-hydroxy-carboxylic acid amides of the general formula wherein R represents hydrogen, methyl or ethyl, R rep resents hydrogen, an alkyl monocarboxy acyl radical con'- taining from 1 to 5 carbon atoms, inclusive, or an alkyl dicarboxy acyl radical containing from 2 to 5 carbon atoms, inclusive, R stands for hydrogen or an alkoxy radical containing from 1 to 4 carbon atoms, inclusive, and R and R represent alkyl radicals containing from 1 to 4 carbon atoms, inclusive, which, apart from their useful thereapeutic properties, are distinguished by their very low toxicity.

The present invention relates also to the preparation of such 'yrhydroxywarboxylic acid amides, for example, by a (a) Reacting the amines of the formula .wherein R R and R have the meaning given above,

With y-1act0nes of the general formula R oH oHz on.-o=o

wherein R has the meaning given above, and if necessary or desired, acylating the v-hydroxy group present in these products, or by 2 (c) Treating with nitrous acid 'y-amino-carboxylic acid amides of the formula R4 ROH-CH:CH7C ONH-CH3(IJV'RI NH: I

wherein R, R R and R have the meanings given above, and, if necessary or desired, acylating the y-hydroxy groups present in these products, or by (d) Exchanging boxylic acid amides of the formula a RCH-CH2-OH2C O-NH-OHg-(f-R:

wherein R, R R and R have the meanings'given above, the halogen atom for the acyloxy or hydroxy group, and, if necessary or desired, separating by hydrolysis the O- acyl group present, and finally, the preparation of such 'y-hydroxy-carboxylic acid amides also succeeds by (e) Reducing the corresponding y-oxo-carboxylic acid amides of the formula be present in the form of amides which are usable as starting substances are for example: 2-phenyl-2-methylbutyl-amine (1), 2-(0rtho-, metaor para-methoxy or -ethoxy-phenyl) -2methyl-butylamine-( 1), -2 phenyl 2- ethyl-butyl-amine-(1),,2-(0rtho-, meta- 01' para-,methoxy or -propoxy-phenyl) -2-ethyl-butylamine-( 1 2 -phenyl-2 propyl-butylamine-(l), 2- (ortho-, metaor para-methoxy or -butoxy-phenyl)-2 propy1-butylamine-(1), 2-phenyl-2-"- isopropyl-butylamine-(l), 2-(ortho-, metaor para-meth oxy or -allyloxy-phenyl)-2-isopropyl-butylamine-(1), 2 phenyl-Z-butyl-butylamine-(l), 2-(ortho-,meta'- or paramethoxyor -ethoxy-phenyl)-2-buty1-butylamine-(l) 2 i phenyl-2-isobutyl-butylamine- (1), 2-,(ortho-, meta or para-methoxy or -isobutoxy-phenyl) 2 isobutyl butyl- -amine-( l 2-phenyl-2-sec.butyl-butylamine( 1) 2-(o'rtho-, metaorpara-methoxy or -ethoxy-phenyl)-2-sec. butyl-butylamine-( 1), it being possible that instead of -butylamine-(1) there may also stand -propylamine-(l),'

-amylamine-( l) or -hexylamine-( 1 Particularly advantageous is the use of such amines in which at least one 7 of the two radicals R and R is an ethyl radical; The

mentioned amines can be obtained by known processes, for example, by hydrogenation of the nitriles concerned.

As 'y-hydroxy-carboxylic acid amides that may be re acted, for example, in the form of esters, with the amines, i there come into consideration: 'y-hydroxybutyric'acid, 'y -i hydroxyvaleric acid and -hydroxycapronic acid. The,

- -hydroxy group may be esterified, for example, with the following carboxylic acids: formic acid, acetic acid,

propionic acid, butyric acid, isobutyric acid or Valerie 3,045,043,v Patented July 17, 196 2,

in corresponding 'y-halogeno-car-.

acid. In this case, i.e. for the preparation of the desired acid amides, -it is of particular advantage to use the corresponding ac'id halides in causing them to act in known manner at a lower or at a moderately elevated temperature on the amines concerned. The reaction mostly proceeds without it being necessary to provide heat from the exterior; on the contrary, in most cases one operates under cooling with ice at temperatures in the range of and C.; the reaction, however, also succeeds at higher temperatures. The reaction can be carried out either in the presence or in the absence of a solvent. As such are suitable especially ethers such as diethyl ether, diisopropyl ether or dibutyl ether, tetrahydrofurane, dioxane; liquid ketones such as acetone, methyl-ethylketone; hydrocarbons such as petrol ether, benzene, toluene; dimethylformamide.

For binding the hydrogen chloride set free during the reaction, there may be applied an excess of the amine used for the reaction or a tertiary amine such as trimethylamine, triethylamine, dimethylaniline, pyridine-eventually used simultaneously as solventor an alkali metal or alkaline earth metal hydroxide or carbonate. The reaction products are isolated in conventional manner and purified either by crystallization or distillation.

As 'y-hydroxy or -acyloxy-carboxylic acid esters that may be used for the reaction there enter into consideration preferably low molecular weight alkyl or phenol esters.

The reaction usually takes place upon heating of the two components, if necessary or desired, in the presence of suitable solvents. Working up is effected by distillation of the solvent and the excess of reactants and recrystallization or distillation of the residue. If desired, the O-acyl group of the -acyloxy-carboxylic acid amides obtained can be separated by treatment with dilute alkalies or acids.

A particularly advantageous method of carrying out the process of the present invention consists in reacting 'y-butyrolactone, -valerolactone or 'y-caprolactone with the amines indicated, the use of the first mentioned lactone being of special advantage. Suitably, the lactone is heated together with the amine concerned for a short time to temperatures above 100 C., the use of a solvent being not necessary. The termination of the reaction can be easily recognized when the reaction mixture practically does no more contain any free amine. In some cases the reaction mixture solidifies upon cooling to a crystal mass which may then be purified by recrystallization. Distillation, however, is also a suitable method of purification of the crude reaction products, but it is carried out suitably under reduced pressure.

Furthermore, the 'y-hydroxy-carboxylic acid amides may also be prepared from 'y-amino-carboxylic acid amides that are obtainedby conventional methods. To these q-aminocarboxylic acid amides which contain the desired substituent at the amide nitrogen atom, one adds dropwise, in the presence of a dilute mineral acid, preferably hydrochloric or sulfuric acid and while stirring and, if necessary, while cooling, the equimolar quantity of an alkali nitrite, preferably sodium nitrite. The evolution of nitro-' gen which indicates the conversion of the amino group into the hydroxy group generally begins upon warming to room temperature. The reaction mixture is subsequently stirred for some time at room temperature or, if necessary, at a slightly elevated temperature (for example, on the steam bath) until the evolution of gas ceases and the conversion of the amino group into the hydroxy group is terminated.

The conversion of the amides of 'y-halogeno-carboxylic acids that enter into consideration, for example, of the 'y-chlorobutyric acid, 'y-bromobutyric acid, wiodobutyric acid and the corresponding 'y-halogeno-valeric and qhalogeno-capronic acids, into the desired 'y-hydroxycarboxylic acid amides is likewise realized in a manner as such known. The hydrolysis of the halogen atom is preferably carried out in an alkaline medium, for example, by the action of dilute caustic alkali solution or aqueous alkali carbonate solution either in the cold or in the heat. Silver hydroxide or another heavy metal hydroxide may be used with special advantage. The replacement of the halogen atom by an acyloxy group is preferably effected by the reaction with alkali salts of such low molecular weight aliphatic carboxylic acids as are mentioned above; in some cases the silver or copper salts of those acids are especially suitable. In order to separate the O-acyl group, the -acyloxy-carboxylic acid amides obtained can be hydrolyzed in conventional manner, for example, by treatment with dilute alkalies or acids.

As oxo-carboxylic acid amides that may be used in the process of the present invention there enter into consideration amides formed from one of the amines mentioned hereinbefore and the -oxo-butyric, -valeric and -capronic acids, respectively, which can be obtained by conventional methods, for example, from corresponding esters. The oxo-group can be reduced, for example, catalytically with the aid of metals of the 8th group of the periodic system, preferably with nickel catalysts in the presence of solvents conventionally used therefor such as aqueous alcohols, alcohols or water. There may also be used noble metals or Raney catalysts. It is also possible to carry out the reduction with nascent hydrogen, for

example, with aluminum amalgam and alcohol, sodium amalgam, lithium-aluminum hydride or sodium-boron hydride. The reduction may also be realized by way of electrolysis.

As has been already stated, the fY-BCYIOXY-CaIbOXYIiC acid amides can be saponified, if desired, in usual manner to v-hydroxy-carboxylic acid amides. On the other hand, the carboxylic acid amides containing a free 7- hydroxy group can be acylated in a manner as such known,

for example, by operating with halides or anhydrides of low molecular weight carboxylic acids under conventional acylation conditions. The one-side esterification of corresponding y-hydroxy-carboxylic acid amides with dicarboxylic acids is of special advantage. In such cases, it is of advantage, in view of the use of the product in the therapeutic practice, to neutralize in conventional manner the other free carboxy group; the salts so obtained, in particular the alkali metal salts possess a considerably increased water-solubility. As such dicarboxylic acids there are preferably suitable succinic acid, maleic acid and glutaric acid.

It is of advantage to operate with the anhydrides of dicarboxylic acids which, if desired in the presence of an organic solvent, for example even pyridine, are caused to act on the 'y-hydroxy-carboxylic acid amides. It may be of advantage in this case to provide heat.

The products obtained by the process of the present invention, i.e. the v-hydroxy-carboxylic acid amides containing a free hydroxy group as well as the corresponding acylated compounds, are valuable medicaments which possess very favorable therapeutic properties and a low toxicity. Depending on the dose administered, they are suitable as very good sedatives, hypnotics or narcotics.

In order to test them for their narcotic properties, the products are intravenously injected to mice in the form of a solution of 0.5% in propylene glycol of strength. By an intravenous injection of 30 mg./kg. of

' -hydroxy butyric acid-[2-(m-methoxy-phenyl)-2-ethylbutyl-(1)]-amide the mice were narcotized; they quietly remained on their backs. The administration of the mentioned dose caused a narcosis lasting about 10-15 minutes. The injection of 40 mg./kg. produced a narcosis lasting about 15-20 minutes. When using rats as experimental animals, the intravenous injection of 20 mg./kg. of the compound mentioned in the form of a solution of 5% in propylene glycol of 100% strength likewise produced a narcosis lasting for about 5-10 minutes and during which the animals could be turned on the back and remained in that position. Accordingly,

50 mg./kg. produced in rats a prolonged effect, the period of the narcosis amounting to about 30 minutes. In the dog, intravenous injection of a solution of in propyleneglycol of 100% strength containing mg./kg. of the compound mentioned produced a deep quiet narcosis which began 1 minute after the injection. The postural reflexes had ceased whereas the corneal reflexes remained elicitable and the dorsal decubitus remained too. The greatest depth of the narcosis lasted for about 30 minutes. One hour after the injection, the dogs ran about again. It is, in this connection, of special importance that the dogs slept in and Woke up free from excitation. mg./kg., injected intravenously, produced a quiet narcosis setting in during the injection and lasting for about 45 minutes. A particular advantage for the use of these compounds as medicaments is their relatively low toxicity. In rats, the LD after intravenous application of the above-mentioned compounds in form of a solution of 5% strength in pure propylene glycol, amounted to 70 mg./kg. The LD in mice amounted under otherwise equal application conditions to 55 mg./kg.

For the therapy of humans, there enter into considerations dosages in the range of 0.1 gram and 23 grams of the products of this invention.

The compounds may be used as such or in the form of pharmaceutical preparations. For preparing such pharmaceutical preparations, there may be used the conventional galenic auxiliary substances, for example, water, lactose, starch, gelatin, magnesium stear ate, talcum, rubber, plant oils, polyalkylene glycols, and the like. As forms of preparation enter into consideration tablets, dragees, capsules, ampoules, drops and suppositories. These pharmaceutical preparations can be sterilized and/ or contain stabilizing, Wetting or bulfer substances. They may also be mixed or combined with other pharmaceutically active substances.

The following examples serve to illustrate the invention but they are not intended to limit it thereto.

EXAMPLE 1 y-Hydroxy-Bu tyric Acid- [2-Phenyl-2-Ethyl-Butyl-(1 Amide A mixture of 13.5 grams of 'y-butyrolactone and 27.8 grams of 2-phenyl-2-ethyl-butylamine-(1) is heated for about 7 hours to 110120 C., After cooling there is obtained ,a viscous oil which upon inoculation solidifies to a crystal mass. The product is triturated with a small quantity of ether. There are obtained 36.5 grams of 'yhydroxy-butyric acid- [Z-phenyI-Z-ethyl-butyl-( 1 ]-amide. After recrystallization from a mixture of petrol ether and acetic ester, the product melts at 70-71 C.

EXAMPLE 2 'y-Hydroxy-Butyric Acid-[Z-(m-Methoxy-Phenyl) -2-Ethyl- Butyl-(I ]-Amide A mixture of 9 grams of 'y-butyrolactone and 20.7 grams of 2-(m-methoxy-phenyl)-2-ethyl-butylamine-(1) is heated for 10 hours to 120-125 C. After cooling and with water, is then shaken with a dilute potassium carbonate solution and the alkaline extract is then sucked off with active charcoal; by acidification there is obtained an'oil which is separated with ether; After evaporation of the ether solution which has been dried with sodium sulfate, there is obtained the 'y-succinoxy-butyric acid-[2- phenyl-2-ethyl-butyl-(l)l-amide (35 grams) the for m 11.8 grams of y-hydroxy-butyric acid-[2-(m-methoxyphenyl)-2-ethyl-'butyl-(1)]amide and 5.8 grams of succinic acid anhydride in 6 cc. of pyridine are heated under exclusion of air moisture on the steam bath, and the reaction solution is worked up in the manner described in Example 3. There are obtained 14.1 grams of -succinoXy-butyric acid-[Z-(m-methoxy-phenyl)2-ethyl-butyl- (1)]-amide in the form of a colorless viscous oil which is converted into the hygroscopic sodium salt by dissolution in a calculated amount of sodium carbonate and lyophilization of the neutral solution.

A nalysis.C H NO Na 5. Calculated: CH O=7.45% Found: CH O=7.5%

EXAMPLE 5 v 'y-Hydroxy-Valeric Acid- [Z-PhenyI-Z-Ethyl-Butyl- (I ]-Amide A mixture of 20 grams of 'y-valerolactone and 35.4 grams of 2-phenyl-2-ethyl-butylamine-(l) is heated for several hours to 130 C. The reaction mixture is dissolved in ether. After inoculation and cooling'with ice, there are obtained 45 grams of -hydroxy-valeric acid- [2-phenyl-2-ethyl-butyl-(1)]-amide melting at 83-84" C.

1 EXAMPLE 6 'y-Hydroxy-Valeric Acid-[Z-(m-Methoxy Phenyl) -2- Ethyl-Butyl-(1)]-Amide 20 grams of 'y-valerolactone are reacted with 41.4 grams of Z-(m-methoxy-phenyl)Q-ethyLbutylamine-(l) by heating for several hours to 125135 C. By distillation of the reaction mixture there are obtained 32 grams of 'y-hydroxy-valeric acid-[Z-(m-methoxy-phenyl) -2-ethylbutyl-(1)]-amide in the form of a light yellow viscous oil having a boiling point of 180-183" C. under 0.1 Hg pressure.

Analysis. C H NO (307.4). Calculated: N=4.6%;

A CH O=10.1%; Found: N=4.6%; CH O=l0.0%.

inoculation there is then obtained a crystal mass which is triturated with a mixture of ether and petrol ether. There are obtained finally 20 grams of v-hydroxy-butyric acid-[2-(m-methoxy-phenyl) 2 ethyl-butyl-(1)]-amide. The compound melts after recrystallization from ether at EXAMPLE 3 'y-Succinoxy-Butyric Acid- [Z-Phenyl-Z-Ethyl-Butyl-(1 Amide 26.3 grams of 'y-hydroxy-butyric acid-[2-phenyl-2-ethylbutyl-(1)]-amide and 14.5 grams of succinic acid anhydride are heated under exclusion of air moisture in 15 cc. of pyridine for one hour on the steam bath. The reaction solution is then allowed to cool, diluted with water and shaken out with ether. The ether solution, which is washed with dilute hydrochloric acid and subsequently EXAMPLE 7 'y-Hydroxy-Capronic Acid-[Z-Phenyl-Z-Ethyl-Butyl- (1 ]-Amide e I 0011, (References on following page) Australia Feb. 11, 1959 France Feb. 23, 1959 Germany May 16, 1957 Great Britain Aug. 14, 1957 Great Britain June 10, 1959 Great Britain July 8, 1959 OTHER REFERENCES Hacklfs Chemical Dictionary, 3rd Ed., The Blakiston 10 Co. (Philadelphia, 1944), page 18.

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